Mechanistic elucidation guided by covalent inhibitors for the development of anti-diabetic PPARγ ligands.

ABSTRACT: Peroxisome proliferator-activated receptor gamma (PPARγ) is a ligand-regulated transcription factor that plays crucial roles in adipogenesis, lipid metabolism, and glucose homeostasis. Several PPARγ ligands possess anti-diabetic activity and they commonly inhibit the phosphorylation of PPARγ at serine 273 (Ser273). The recently reported PPARγ ligand SR1664, which selectively blocks the phosphorylation of PPARγ without classical agonism, has potent anti-diabetic activity, indicating that the inhibition of Ser273 phosphorylation is sufficient to provoke anti-diabetic effects. In this study, we revealed the X-ray structure of PPARγ co-crystallized with SR1664 bound to the alternate binding site of PPARγ and confirmed that the alternate site binding of SR1664 blocks the phosphorylation of Ser2

SUBMITTER: Bae H 

PROVIDER: S-EPMC6021786 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature